Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
BackgroundThe detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29 years by the National Institutes for Health (NIH) criteria which include ≥ 6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria.MethodsWe have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥ 6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009–12/2015 on 361 NF1 patients.FindingsA presumed causative NF1 mutation was found in 166/171 (97.08%–95% CI 94.56–99.6%) of familial cases and 182/190 (95.8%–95% CI 92.93–98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p = 0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥ 6 CAL and no non-pigmentary criterion aged 0–20 years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥ 6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis.InterpretationRNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥ 6 CAL that they are unlikely to have NF1.
The eyes of 64 patients known to have neurofibromatosis were examined. Lisch nodules were the commonest manifestation of the disease and were present in 95% of all patients (100% of those aged 16 years or older). Neurofibromatosis was first described by von Recklinghausen in 1882.' A wide range of complications of the disease are now recognised, and it has become apparent that there are several forms of neurofibromatosis. The one described by von Recklinghausen is by far the most common and is now referred to as von Recklinghausen or peripheral neurofibromatosis. The other forms include central neurofibromatosis, the major defining features of which are bilateral acoustic neuromas with few if any cutaneous manifestations, and segmental neurofibromatosis, where the features of the peripheral form are confined to one segment of the body.2 Von Recklinghausen neurofibromatosis (NF) is an autosomal dominant disorder with a high mutation rate and a prevalence of around 30/100 000 of the population.3 There is no laboratory test for NF and the diagnosis is made on the basis of the major defining features of the disease-cafe au lait spots and cutaneous neurofibromas. Cafe au lait spots are flat light brown patches which vary in size from a few millimetres to several centimetres. They begin to develop at or soon after birth and increase in number and size throughout childhood. Some patients with NF also develop axillary freckling, a clinical sign unique to the disease. Cutaneous neurofibromas begin to appear about the time of puberty and increase in number throughout life. Approximately 25% of patients with NF develop complications which include plexiform neurofibromas, malignancies (of which neurofibrosarcomas and embryonic childhood tumours are the most frequent), scoliosis, congenital bone defects, and tumours of the central nervous system.4 The complications of NF that may present to the ophthalmologist are optic gliomas, plexiform neurofibromas Correspondence to Mr D Jones.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.